Therapeutic applications of artificial cerebrospinal fluid and tools provided therefor

ABSTRACT

Described herein is the use of CSF, more particularly external CSF or CSF-like compositions for the treatment and prevention of different diseases. More particularly, the application provides for the administration of CSF to the intrathecal space or the cerebral ventricles of a patient to increase intracranial pressure and/or CSF flow.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/517,983, filed Apr. 10, 2017, now U.S. Pat. No. 10,874,798 B2, issuedDec. 29, 2020, which is a U.S. national stage entry under 35 U.S.C. §371 of PCT International Patent Application No. PCT/EP2015/073893, filedOct. 15, 2015, which claims priority to U.S. Provisional PatentApplication No. 62/064,321, filed Oct. 15, 2014 and European PatentApplication No. 15163949.9, filed Apr. 17, 2015, the contents of whichare incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present application one the one hand relates generally to the fieldof cerebrospinal fluid and its use locally in the brain and/or the spineto increase intracranial pressure and/or cerebrospinal fluid (CSF)turnover. The application relates to Alzheimer's disease and methods andmedical devices for the treatment thereof. More particularly, theapplication provides methods and tools for treating and/or preventingAlzheimer's disease by increasing CSF turnover. The application furtherrelates to glaucoma and methods and medical devices for the treatmentthereof. More particularly, the application provides methods and toolsfor treating and/or preventing glaucoma by increasing intracranialpressure and/or CSF turnover.

The present application also relates generally to the field of medicaldevices. More particularly, it relates to implantable, pump-assisteddevices, capable of infusing fluid (e.g. to infuse artificialcerebrospinal fluid) from a reservoir into a bodily cavity. Theapplication more particularly provides implantable, pump-assisteddevices, capable of increasing intracranial pressure and/or CSFturnover. Such devices are of interest in the treatment and/orprevention of glaucoma and in the treatment of Alzheimer's disease andthe treatment of neurological disorders in which inflammatory mediatorsor neurotoxins are involved.

BACKGROUND

The brain and spinal cord are encased within the cranium and vertebralcolumn inside a thin membrane known as the arachnoid. The volume of theintracranial space is on average about 1700 ml including volumes ofapproximately 1400 ml of brain, approximately 150 ml of intracranialblood; and approximately 150 ml of CSF. CSF circulates within thesubarachnoid space and is formed principally by the choroid plexuses,which secrete about 80% of the total volume. The sources of theremainder of CSF are the vasculature of the subependymal regions, andthe pia mater. The total volume of CSF is renewed several times per day,so that about 500 ml are produced every 24 hours.

CSF is absorbed through the arachnoid villi, located principally overthe superior surfaces of the cerebral hemispheres. Some villi also existat the base of the brain and along the roots of the spinal nerves. Theabsorptive processes include bulk transport of large molecules and aswell as diffusion across porous membranes of small molecules. See, e.g.,Adams et al., (1989) “Principles of Neurology,” pp. 501-502.

There are several examples of low-molecular weight proteins or peptidesthat are known to be present in altered concentrations in CSF of personssuffering from adult-onset dementia of the Alzheimer's type. Alzheimer'sdisease, the most common type of dementia, is characterizedneuropathologically by the presence in the brain of extracellular senileplaques and intracellular neurofibrillary tangles, along with neuronalcell loss. The major component of senile plaques is the low molecularweight peptide beta-amyloid. Neurofibrillary tangles are mainly composedof abnormally phosphorylated tau protein. Studies consistently reportdecreased levels of beta-amyloid (1-42) in CSF from Alzheimer patientsin comparison with healthy subjects. See, e.g., Engelborghs et al.,(2008) “Diagnostic performance of a CSF-biomarker panel inautopsy-confirmed dementia,” Neurobiol. Aging 29:1143-1159. Beta-2microglobulin is another example of a low-molecular-weight protein whoseconcentration in CSF increases with age and reaches high levels inpatients with adult-onset dementia of the Alzheimer's type, as reportedin Martinez et al., (1993) “Relationship of interleukin-1 beta andbeta.sub.2—microglobulin with neuropeptides in cerebrospinal fluid ofpatients with dementia of the Alzheimer type,” J. Neuroimmunology 48:235-240. Beta-2 microglobulin is associated with amyloid deposits insome tissues of patients on long-term renal hemodialysis. Anothersubstance that accumulates in CSF in patients with adult-onset dementiaof the Alzheimer's type is tau, a component of the neurofibrillarytangles found in involved brain tissue. Tau concentrations in CSF areregularly increased in this syndrome with eight fold increases presentin half of the patients, as reported in Arai et al., (1995) “Tau incerebrospinal fluid: a potential diagnostic marker,” Ann. Neurology 38:649-52.

Other neurological diseases are characterized by the presence ofinflammatory mediators or neurotoxins, such as central nervousinfection, ischemic stroke, subarachnoid hemorrahge, intracerebralhemorrahge, multiple sclerosis, Parkinson's disease traumatic injuriesand epilepsy. All of these diseases could theoretically benefit frommethods which involve increased CSF turnover and the removal of theconcentration of these mediators or toxins.

Previously-known devices have attempted to use filtration techniques toremove or reduce concentrations of harmful proteins from patient bodyfluids. For example, U.S. Pat. No. 5,334,315 to Matkovich describes amethod and device that may be used to remove a body fluid from apatient, treat that fluid to remove an undesirable component, and returnthe fluid to the patient. Matkovich includes a partial list of the typesof deleterious or undesirable substances that may be removed from afluid, such as proteins, polypeptides, interleukins, immunoglobulins,proteases and interferon. The fluids from which these substances may beremoved are described as including CSF, blood, urine and saliva,however, Matkovich does not suggest that his method and device could beused to treat patients suffering from adult-onset dementia of theAlzheimer's type.

Glaucoma is one of the leading causes of irreversible blindness. Themost common type of glaucoma is primary open-angle glaucoma (POAG),which is a progressive optic neuropathy with characteristic structuralchanges in the optic nerve head and corresponding visual field defects.In the glaucomatous optic nerve, cupping of the optic disc reflects aloss of retinal ganglion cell (RGC) axons and a posterior bowing of thelamina cribrosa (forming the anatomic floor of the optic nerve head),accompanied by extensive remodeling of the optic nerve head.

Raised intraocular pressure is recognized as one of the most importantrisk factors for POAG and lowering it remains the only currenttherapeutic approach for slowing optic nerve damage and visual fieldprogression in glaucoma patients. Known glaucoma therapies includemedicines (e.g., prostaglandin analogues, beta-blockers, carbonicanhydrase inhibitors, and alpha-agonists), laser surgery (e.g., lasertrabeculoplasty), and incisional surgery (e.g., trabeculectomy, deepsclerectomy, viscocanalostomy, and glaucoma drainage implants).

Therapy typically starts from the least invasive options, which usuallyinvolve the administration of medication. However, the administration ofmedication often fails for various reasons. Indeed, medicaments for thetreatment of POAG typically lower the IOP by at most about 25% to 30%,which can be insufficient. Some glaucoma patients show diseaseprogression despite of the administration of medicaments. Moreover,topical medications for glaucoma can cause side effects such asprecipitation of asthma, bradycardia, impotence, and decreased exercisetolerance. There is also a significant problem in compliance withglaucoma medications due to frequent dosing regimens.

Incisional surgery is usually required when (topical) glaucomamedication and/or laser surgery fail. However, current incisionalsurgery techniques for treating glaucoma can lead to variouscomplications including but not limited to choroidal effusion, hypotonymaculopathy, suprachoroidal haemorrhage, and bleb infections.

Accordingly, there is a need for an alternative glaucoma treatment whichmitigates at least one of the above problems.

A number of implantable pumps have been described in the art. U.S. Pat.Pub. No. 2005/0090549 (Hildebrand et al.) describes a system and methodthat may be used to treat pain by administering gabapentin tocerebrospinal fluid (CSF) of a patient. The system includes a pump, acatheter and a reservoir containing an effective amount of gabapentin totreat pain in the patient by pumping the gabapentin through the catheterinto CSF. U.S. Pat. Pub. No. 201110021469 (Meythaler et al.) describesintrathecal delivery of baclofen to reduce spasticity. Meythalerdescribes using refillable programmable pump systems that areimplantable and provide continuous infusion of baclofen directly intoCSF of a patient. However, neither Hildebrand nor Meythaler disclose orsuggest a method or system which involves increasing intracranialpressure and/or CSF turnover, nor suggest the use of such a system totreat glaucoma and/or Alzheimer's disease.

SUMMARY OF THE INVENTION

The present disclosure provides a fluid infusion system, and methods ofuse, that reduce the concentration of or eliminate undesirable proteinsfrom CSF and/or increase intracranial pressure by delivering artificialCSF or CSF-like solutions to the subarachnoid region and replenishingdepleted CSF to enhance CSF turnover. In particular, it is believed thatadministration of artificial CSF or CSF-like solutions enhances CSFturnover. Therefore, by delivering artificial CSF or CSF-like solutions(optionally containing therapeutic agents) to CSF of patients sufferingfrom Alzheimer or other neurological diseases involving inflammatoryagents CSF turnover will be enhanced while the therapeutic agentsinhibit or eliminate toxic proteins from CSF. Alzheimer patients showlow concentrations of beta-amyloid (1-42) in their CSF compared to CSFof age-matched controls, which is inversely correlated with an increasein the amyloid burden in the brain interstitial fluid. This is thoughtto be due to increased aggregation, fibril and plaque formation, withdecreased clearance of these peptides from the central nervous system.See, Silverberg et al., (2003) “Alzheimer's disease, normal-pressurehydrocephalus, and senescent changes in CSF circulatory physiology: ahypothesis,” Lancet Neurol 2(8):506-511. Furthermore, beta A-4 amyloidhas been shown to be neurotoxic, as described in Bush et al., (1992)“Beta A-4 amyloid protein and its precursor in Alzheimer's disease,”Pharmac. Tera. 56: 97-117. In patients suffering from Glaucoma, theadministration of artificial CSF or CSF-like solutions increasesintracranial pressure and CSF turnover.

Also provided herein is an apparatus for infusing fluid into a bodycavity, more particularly the intrathecal or subarachnoid space or thecerebral ventricles, the apparatus comprising:

-   -   an implantable pump;    -   a reservoir containing artificial cerebrospinal fluid;    -   an infusion catheter having an inlet end coupled to the        reservoir, and an outlet end coupled to the implantable pump;        and    -   an inflow catheter having an outlet end configured to be        disposed in fluid communication with a body cavity, and an inlet        end coupled to the implantable pump;

wherein the implantable pump is configured to selectively moveartificial cerebrospinal fluid from the reservoir through the infusioncatheter and the inflow catheter to the intrathecal space or thecerebral ventricles at a rate and volume sufficient to increase theintracranial pressure and/or the cerebrospinal fluid turnover in apatient.

In particular embodiments, the apparatus further comprises amicrocontroller that controls operation of the implantable pump. Inparticular embodiments, the apparatus comprises a pressure sensordisposed in communication with the inflow catheter to monitor pressureof cerebrospinal fluid, wherein the microcontroller is configured toactivate the implantable pump responsive to an output of the pressuresensor.

In some embodiments, the apparatus may include a microcontroller forcontrolling the operation of the pump and may be responsive to apressure sensor and/or a clock. The pressure sensor may provideinformation regarding the pressure of CSF within the cerebral ventricle.In this manner, the microcontroller may be programmed to pump artificialCSF from the reservoir to the cerebral ventricle only when the pressureof CSF falls below a predetermined value. Alternatively, themicrocontroller may be programmed to pump CSF and artificial CSF orCSF-like solutions in predetermined volumes or at predeterminedintervals, which may be titrated for each patient.

In particular embodiments the microcontroller is configured to activatethe implantable pump so as to ensure a CSF pressure of between 11 and 16mm Hg, more particularly an ICP of about 15 mm Hg, when measured in thelateral decubitus position. In particular embodiments, the apparatuscomprises a feedback mechanism based on said pressure sensor, whichensures that the CSF pressure does not exceed 15 mm Hg. In particularembodiments the microcontroller of the apparatus ensures an increasedCSF turnover. In particular embodiments, the CSF turnover is increasedto about 4.0 volumes/day.

In particular embodiments of the apparatus envisaged herein, thereservoir contains artificial cerebrospinal fluid. In further particularembodiments, the artificial CSF or CSF-like solutions may comprise oneor more therapeutic agents.

In accordance with one aspect of the present invention, the apparatuspreferably comprises an implantable electromechanical pump, an infusioncatheter, an inflow catheter, a reservoir housing artificial CSF orCSF-like solutions, and a one-way valve. The pump, which in a preferredembodiment may be a positive displacement gear pump, may be located inthe chest or abdomen of the patient or external to the patient's body,is configured to transfer fluid from the infusion catheter to the inflowcatheter. The infusion catheter is configured to connect the reservoirto the pump. The inflow catheter is configured to connect the pump to acerebral ventricle or intrathecal space around the spinal cord of apatient. The inflow catheter may be sealed to the cerebral ventricleand/or the spine with a flange. The reservoir may be secured to a holderand worn by the patient like a belt or connected to the infusioncatheter like an IV bag. The one-way valve is configured to permitartificial CSF or CSF-like solutions to flow in one direction: away fromthe infusion catheter and towards the brain or spine. The inflow andinfusion catheters may be sealed to the cerebral ventricle and/or thereservoir with a flange. Additionally, the artificial CSF or CSF-likesolutions may contain therapeutic agents.

In accordance with another embodiment of the present invention, thereservoir may be implantable under the skin of the patient. Theimplantable reservoir comprises a septum to be pierced by a needle forrefilling of artificial CSF or CSF-like solutions.

In accordance with another aspect of the present invention, the systemmay comprise a bacterial filter on or within the infusion catheter orthe inflow catheter to prevent bacteria from passing through the systemto the brain. The bacterial filter may comprise an ultraviolet lightmodule configured to irradiate fluid passing through the filter.Alternatively, some or all of the system components may be coated withor impregnated with antibiotic or antimicrobial coatings or deposits toprevent infection.

In accordance with another aspect of the present invention, theartificial CSF or CSF-like solution delivered to the subarachnoid regionof the patient could be absorbed naturally by the arachnoid villi.

The implantable device may include a rechargeable power source, such asa battery. In accordance with another aspect of the present invention,the system may include an extracorporeal controller configured totransmit energy to the implantable components, communicate informationto the implantable components, and/or receive data from the implantablecomponents.

Further described herein is an apparatus for infusing artificialcerebrospinal fluid (CSF) to the CSF of a patient, in order to increasethe intracranial pressure and/or the cerebrospinal fluid turnover insaid patient. The principle of the methods and tools described herein isbased on the observation that certain diseases such as but not limitedto glaucoma may be associated with a reduced intracranial pressure(ICP). The present inventor proposes the infusion of artificial CSF orCSF-like solutions for the treatment and/or prevention of such diseases.In particular embodiments this can be achieved through an implantablepump, whereby artificial CSF or a CSF-like solution is infused into theintrathecal space or into the cerebral ventricles. The outlet end of theinflow catheter may be disposed in any region of the spine, includingthe cervical region, the thoracic region, the lumbar region etc. It isenvisaged that this provides a therapeutic effect by increasing the ICPand/or the CSF turnover and clearance. In glaucoma, this provides aprotective effect for the optic nerve by reducing the trans-laminacribrosa pressure difference (TLCPD; i.e. intraocular pressure minusintracranial pressure) and/or by enhancing removal of potentiallyneurotoxic waste products that accumulate in the optic nerve.

Also provided herein are methods of reducing the concentration ofundesirable proteins and/or inflammatory agents or neurotoxins, methodsfor increasing the CSF turnover and/or methods for increasing theintracranial pressure. These methods are of interest in the treatment ofdifferent neurological disorders.

In particular embodiments, the methods comprise the steps of (a)providing a reservoir containing artificial cerebrospinal fluid;providing an infusion catheter coupled to the reservoir and theimplantable pump and an inflow catheter coupled to an implantable pump;coupling the inflow catheter to a region of a body cavity; andactivating the implantable pump to pump the artificial cerebrospinalfluid from the reservoir through the infusion catheter and the inflowcatheter to the body cavity at a rate and volume sufficient toreplenish, flush, or both, a portion of cerebrospinal fluid with theartificial cerebrospinal fluid to reduce the concentration ofundesirable proteins, inflammatory agents or toxins in the cerebrospinalfluid known to contribute to disease. In particular embodiments, thebody cavity comprises the arachnoid membrane, the subarachnoid space,one of the lateral ventricles, or the central canal of the spinal cord.

In particular embodiments, the artificial cerebrospinal fluid comprisesone or more therapeutic agents.

In further particular embodiments, the methods of reducing theconcentration of undesirable proteins and/or inflammatory agents orneurotoxins, methods for increasing the CSF turnover and/or methods forincreasing the intracranial pressure further comprise the step ofmonitoring a pressure of the cerebrospinal fluid within the brain; anddeactivating the pump from pumping artificial cerebrospinal fluid fromthe reservoir to the body cavity when the pressure is greater than apredetermined value. In further particular embodiments, the methodscomprise the step of measuring an artificial cerebrospinal fluid volumedelivered to the body cavity; and deactivating the pump from pumpingartificial cerebrospinal fluid from the reservoir to the body cavitywhen the artificial cerebrospinal fluid volume is greater than apredetermined value. In particular embodiments, the methods comprise thestep of preventing backflow of bacteria through the infusion catheter;irradiating cerebrospinal fluid passing through the infusion catheterwith UV light; or coating or impregnating at least one of theimplantable pump, infusion catheter, inflow catheter or the reservoirwith an antibacterial or antimicrobial agent.

In particular embodiments of the methods, the reservoir is adapted to beimplanted within the patient and configured to receive additionalartificial cerebrospinal fluid from an external source. In particularembodiments, the methods further comprise the step of providing anextracorporeal controller configured to communicate wirelessly with thepump; and operating the controller to program activation of the pump.

In particular embodiments, the application provides methods for treatingAlzheimer's disease or another disease characterized by the presence ofundesirable proteins or neurotoxins by administration of artificial CSFor CSF-like solutions.

Accordingly, the application provides for the use of artificial CSF orCSF-like solutions for the treatment of various conditions. Inparticular embodiments, the application provides artificial CSF or aCSF-like solution for use in the treatment of neurological disorderscharacterized by the presence of undesirable proteins or inflammatoryagents. In particular embodiments, the neurological disorder isAlzheimer's disease. In further particular embodiments, the artificialCSF or CSF-like solution may comprise one or more therapeutic agentswhich reduce or inhibit the undesirable proteins or inflammatory agents.In particular embodiments, the neurological disorder is selected fromcentral nervous system infection, ischemic stroke, subarachnoidhemorrhage, intracerebral hemorrhage, multiple sclerosis, Parkinson'sdisease, traumatic injuries (such as cerebrospinal injury or severetraumatic brain injury), amylolateral sclerosis and epilepsy.

In particular embodiments, the application provides for the use ofartificial CSF or CSF-like solutions in the treatment of glaucoma. Thusalso provided herein are methods and tools for the prevention andtreatment of glaucoma. In particular, the methods comprise increasingintracranial pressure and/or CSF turnover by the administration ofartificial CSF or CSF-like solutions.

Provided herein is a method of prevention and/or treatment of glaucomain a patient which comprises administering artificial CSF or CSF-likesolution directly or indirectly into the cerebral ventricles or theintrathecal space of said patient. More particularly the methodcomprises administering artificial CSF or a CSF-like solution so as toensure an increase in ICP and/or to increase CSF turnover. In particularembodiments, the method comprises reducing the trans-lamina cribrosapressure difference (TLCPD; i.e. IOP minus ICP), preferably to a valueof about 4 mm Hg, or less such as to a value of 2 or 1 mm Hg. Inparticular embodiments, the method comprises ensuring a ICP of between11 and 16 mm Hg, more particularly an ICP of about 15 mm Hg, whenmeasured in the lateral decubitus position. Additionally oralternatively, the methods provided herein comprise ensuring an increasein the total CSF turnover in the patient. The optimal infusion rate ofCSF will be dependent on the natural daily absorption of CSF by thepatient to allow the body to readily absorb CSF and maintain an adequateICP. In particular embodiments, the pump may maintain an infusion rateof the fluid in the range of 0.05-0.1 ml/min, 0.1-0.2 ml/min, 0.2-0.42ml/min, 0.42-0.7 ml/min or even up to 0.7-1.04 ml/min (1.5 L/day). Inparticular embodiments a turnover is ensured of about 4.0 volumes/day.In particular embodiments, the methods comprise administering theartificial CSF or a CSF-like solution to the intrathecal or subarachnoidspace or the cerebral ventricles of said patient by supplementing saidpatient's CSF with artificial CSF or a CSF-like solution. Moreparticularly this is ensured by way of an apparatus capable of infusingfluid with an implantable pump, more particularly artificial CSF or aCSF-like solution directly or indirectly into the intrathecal spaceand/or the cerebral ventricles of said patient.

The above and other characteristics, features and advantages of thepresent invention will become apparent from the following detaileddescription, which illustrates, by way of example, the principles of theinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

The following description of the figures of specific embodiments of theinvention is merely exemplary in nature and is not intended to limit thepresent teachings, their application or uses. Throughout the drawings,corresponding reference numerals indicate like or corresponding partsand features.

FIG. 1A is a schematic view of the implantable components connected to abrain and an external reservoir according to an embodiment of theinvention. FIG. 1B is a schematic view of the implantable componentsconnected to a spinal cord and an external reservoir according to anembodiment of the invention. FIG. 1C is a schematic view of theimplantable components connected to a brain and an implantable reservoiraccording to an embodiment of the invention.

FIG. 2 is a schematic diagram of a fluid infusion system according to anembodiment of the present invention.

FIG. 3 is a perspective view of the outlet end of the inflow catheter ofthe fluid infusion system according to an embodiment of the invention.

FIGS. 4A and 4B are, respectively, a perspective view of the implantablepump for use in the fluid infusion system and a cross-sectional view ofan implantable pump mechanism for use within the fluid infusion systemaccording to an embodiment of the invention.

FIGS. 5A, 5B, and 5C illustrate cross-sectional views of alternativeone-way valves to control the direction of fluid flow within the fluidinfusion system according to an embodiment of the invention.

DETAILED DESCRIPTION

The present invention will be described with respect to particularembodiments but the invention is not limited thereto but only by theclaims. Any reference signs in the claims shall not be construed aslimiting the scope thereof.

As used herein, the singular forms “a”, “an”, and “the” include bothsingular and plural referents unless the context clearly dictatesotherwise.

The terms “comprising”, “comprises” and “comprised of” as used hereinare synonymous with “including”, “includes” or “containing”, “contains”,and are inclusive or open-ended and do not exclude additional,non-recited members, elements or method steps. The terms “comprising”,“comprises” and “comprised of” when referring to recited components,elements or method steps also include embodiments which “consist of”said recited components, elements or method steps.

Furthermore, the terms “first”, “second”, “third” and the “like” in thedescription and in the claims, are used for distinguishing betweensimilar elements and not necessarily for describing a sequential orchronological order, unless specified. It is to be understood that theterms so used are interchangeable under appropriate circumstances andthat the embodiments of the invention described herein are capable ofoperation in other sequences than described or illustrated herein.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment of the present invention. Thus, appearances of the phrases“in one embodiment” or “in an embodiment” in various places throughoutthis specification are not necessarily all referring to the sameembodiment. Furthermore, the particular features, structures orcharacteristics may be combined in any suitable manner, as would beapparent to a person skilled in the art from this disclosure, in one ormore embodiments. Furthermore, while some embodiments described hereininclude some but not other features included in other embodiments,combinations of features of different embodiments are meant to be withinthe scope of the invention, and form different embodiments, as would beunderstood by those in the art. For example, in the appended claims, anyof the features of the claimed embodiments can be used in anycombination.

The values as used herein when referring to a measurable value such as aparameter, an amount, a temporal duration, and the like, is meant toencompass variations of +/−10% or less, preferably +/−5% or less, morepreferably +/−1% or less, and still more preferably +/−0.1% or less ofand from the specified value, insofar such variations are appropriate toperform in the disclosed invention. It is to be understood that eachvalue as used herein is itself also specifically, and preferably,disclosed.

The recitation of numerical ranges by endpoints includes all numbers andfractions subsumed within the respective ranges, as well as the recitedendpoints.

All documents cited in the present specification are hereby incorporatedby reference in their entirety.

CSF flows from the brain ventricles into interconnecting chambers,namely, the cisterns and the subarachnoid spaces (SASs), including theSAS of the optic nerves. The optic nerve, a white matter tract of thecentral nervous system, is ensheathed in all three meningeal layers andsurrounded by cerebrospinal fluid (CSF) in the subarachnoid space (SAS)with a pressure equivalent to intracranial pressure (ICP). Thus, inaddition to intraocular pressure (IOP), the optic nerve is exposed tothe ICP. The lamina cribrosa, the perforated region of the sclerathrough which the nerve fibers of the optic nerve pass as they exit theeye, separates these two pressurized regions. The difference between theposteriorly directed IOP and anteriorly directed ICP across the laminacribrosa is known as the trans-lamina cribrosa pressure difference(TLCPD). The term “intracranial pressure” or “ICP” as used herein thusrefers to the pressure of cerebrospinal fluid (CSF) within the skull andthus in the brain tissue and CSF and is also referred to as “CSFpressure”. The CSF pressure as assessed by lumbar puncture correlateswith ICP, and thus the terms CSF pressure and ICP are usedinterchangeably. The ICP is built up by the equilibrium between theproduction and outflow of CSF. If the intracranial compliance is assumedto be constant, the steady-state ICP can be described by a simplifiedequation: ICP=I_(f)×R_(out)+P_(ss), where I_(f) is CSF formation rate,R_(out) is outflow resistance, and P_(ss) is sagittal sinus pressure.ICP is measured in millimetres of mercury (mmHg). At rest it is normallybetween 5-15 mmg Hg for an adult when measured by lumbar puncture in thelateral decubitus position. Accordingly, the values of ICP (or CSFpressure) referred to herein refer to values when measured in thelateral decubitus position.

The term “intraocular pressure” or “IOP” as used herein refers to thefluid pressure within the eye. It is measured in millimetres of mercury(mmHg). Normally the IOP ranges from 11 to 21 mmHg with a mean of 16mmHg.

The “trans-lamina cribrosa pressure difference” or “TLCPD” is thedifference between the posteriorly directed IOP and the anteriorlydirected ICP across the lamina cribrosa. The pressure drop that occursacross the lamina cribrosa (IOP-ICP) increases with elevation of IOP orreduction of ICP. Indeed, from a mechanical perspective, a similarposteriorly directed force is caused by either a lower pressure on theCSF side of the lamina or a higher pressure on the intraocular side.

A CSF-like solution as used herein refers to a solution that consistsessentially of CSF or artificial CSF.

The term “artificial CSF” (aCSF) as used herein refers to a solutionthat closely matches the electrolyte concentrations of cerebrospinalfluid. Typically, the artificial CSF comprises sodium ions at aconcentration of 140-190 mM, potassium ions at a concentration of2.5-4.5 mM, calcium ions at a concentration of 1-1.5 mM, magnesium ionsat a concentration of 0.5-1.5 mM, phosphor ions at a concentration of0.5-1.5 mM, chloride ions a concentration of 100-200 mM. In one example,the artificial CSF comprises sodium ions at a concentration of 150 mM,potassium ions at a concentration of 3 mM, calcium ions at aconcentration of 1.4 mM, magnesium ions at a concentration of 0.8 mM,phosphor ions at a concentration of 1 mM, chloride ions a concentrationof 155 mM. aCSFs have been described in the art and include, but are notlimited to Elliot's solutions A and B and ARTCEREB™.

Typically where reference is made to the administration of CSF, it isintended to refer to a CSF-like solution or to CSF which is (at leastpartially) of foreign origin (i.e. not from the patient).

In particular embodiments, the CSF may further comprise one or moretherapeutic agents, for example agents for reducing the IOP and/orincreasing the ICP. For example specific peptides such as angiotensinhave been shown to facilitate the rise in CSF pressure upon CSFinfusion.

The term “intrathecal space” also referred to as the subarachnoid space(SAS) is the fluid-filled area located between the innermost layer ofcovering (the pia mater) of the spinal cord and the middle layer ofcovering (the arachnoid mater).

The term “undesirable protein” as used herein refers to proteins whichare characteristically present in the CSF in certain neurologicalconditions and are known to be correlated with the disease, such as, forAlzheimer's disease, tau and beta-amyloid. The term “inflammatory agent”as used herein refers to compounds such as cytokines and enzymes whichmediate inflammation, such as, but not limited to IL-1beta and tumornecrosis factor (TNF)-alpha, IL-6, IL-8, monocyte chemoattractantprotein-1, neutrophil-activating peptide 2, intracellular adhesionmolecule-1, soluble Fas, tissue inhibitors of metalloproteinase 1, andmatrix metalloproteinases-2 and -9.

The term “neurotoxin” as used herein refers to a compound detrimental tothe nervous system that occurs in CSF in certain conditions, such asN-methyl(R)salsolinol in Parkinson's disease and glutamate in certaintypes of epilepsy.

Unless otherwise defined, all terms used in disclosing the invention,including technical and scientific terms, have the meaning as commonlyunderstood by one of ordinary skill in the art to which this inventionbelongs. By means of further guidance, definitions for the terms used inthe description are included to better appreciate the teaching of thepresent invention. The terms or definitions used herein are providedsolely to aid in the understanding of the invention.

The present invention is based on the finding that the intracranialadministration of artificial CSF or CSF-like solutions can be beneficialin the treatment of various diseases, more particularly in diseasescharacterized by the presence of undesirable proteins or inflammatoryagents in the CSF and/or by a reduced intracranial pressure. Moreparticularly it has been found that the administration of artificial CSFor CSF-like solutions can ensure an increase in CSF turnover in additionto increasing intracranial pressure in those conditions where this isbeneficial. The application therefor provides tools for the intracranialadministration of artificial CSF or CSF-like solutions and methods oftreatment involving the administration of artificial CSF or CSF-likesolutions.

Provided herein are methods and devices for treating Alzheimer's. Moreparticularly provided herein are methods and devices for augmenting therate of CSF turnover, for the treatment and/or prevention of Alzheimer'sdisease. More particularly, the methods and tools for the treatment ofAlzheimer's provided herein involve the administration of CSF or aCSF-like solution (such as artificial CSF) directly or indirectly to thecerebral ventricles and/or to the intrathecal space around the spinalcord. By delivering CSF or artificial CSF to the subarachnoid region,the rate of CSF turnover and clearance is increased thereby enhancingremoval of undesirable proteins accumulating in the CSF in patientssuffering from the disease thereby ensuring the treatment of Alzheimer'sdisease. More particularly, the methods and tools provided hereinenhance the removal of proteins such as tau and amyloid-beta whichcharacteristically accumulate in the brain of patients suffering fromAlzheimer's disease.

Provided herein are compositions for use in methods of prevention and/ortreatment of Alzheimer's disease in a patient in need thereof andcorresponding methods of treatment and prevention. More particularly, acomposition comprising CSF or a CSF-like solution such as artificial CSFis provided for use in the prevention or treatment of Alzheimer'sdisease. In particular embodiments, the methods of prevention and/ortreatment of Alzheimer's in a patient comprise administering CSF or aCSF-like solution to the intrathecal space or the cerebral ventricles ofsaid patient. More particularly, the artificial CSF is administered tothe intrathecal space surrounding the spinal cord. Indeed, theadministration of CSF or a CSF-like solution can be done locally, in thecerebral ventricles, but in most embodiments the same effect can beachieved less invasively by infusion more remotely, i.e. intrathecallyanywhere along the spinal cord, including the cervical region, thethoracic region, the lumbar region etc. In particular embodiments, thecompositions for use in the methods described herein comprise, inaddition to artificial CSF one or more therapeutic agents. In particularembodiments, such a therapeutic agent may be an agent which is known toinhibit the aggregation of proteins present in the CSF such asamyloid-beta. Examples of suitable agents capable of inhibitingaggregation of proteins are chaperones, such as but not limited totransthyretin (“TTR”), Cystatin C (“CysC”), beta-trace. Indeed inparticular embodiments it is envisaged to add to the artificial CSF ofCSF like solution chaperones known to be beta-amyloid-binding chaperonesthat are reduced in CSF of persons with Alzheimer's disease. Forexample, lowered CSF levels of transthyretin (“TTR”) are associated withbeta-amyloid and tau accumulation in patients with Alzheimer's disease.See, Maetzler et al., (2012) “Serum and Cerebrospinal Fluid Levels ofTransthyretin in Lewy Body Disorders with and without Dementia,” PLoSONE 7(10): e48042. TTR influences beta-amyloid aggregation and destroysalready formed beta-amyloid fibrils. TTR is one of the majorbeta-amyloid binding and sequestering proteins in human CSF. Patientswith Alzheimer's disease are linked to alterations in the structure ofchoroid plexus in the brain, resulting in a decreased synthesis of TTRin CSF. See, Merched et al., (1998) “Apolipoprotein E, transthyretin andactin in CSF of Alzheimer's patients: relation with the senile plaquesand cytoskeleton biochemistry,” FEBS Letters 452:225-228. Decreasedlevels of TTR in CSF lead to accumulation and aggregation ofbeta-amyloid, beta-amyloid formation, and neurotoxicity.

Cystatin C (“CysC”) is another example of a beta-amyloid-bindingchaperone whose concentration is decreased in CSF of patients withAlzheimer's disease. Lower levels of CysC may result in decreasedability to inhibit neuronal beta-amyloid aggregation and deposition.CysC protects against neurodegeneration by inhibition of beta-amyloidoligomerization and fibril formation. Experimental, genetic, andclinical data suggest that CysC protects against the development ofAlzheimer's disease. See, Zhong et al., (2013) “Alterations of CSFCystatin C Levels and Their Correlations with CSF Aβ40 and Aβ42 Levelsin Patients with Alzheimer's Disease, Dementia with Lewy Bodies and theAtrophic Form of General Paresis,” PLoS ONE 8(1): e55328.

Another beta-amyloid-binding chaperone that has been found to be lowerin CSF of patients with Alzheimer's disease is beta-trace. Beta-trace isa major endogenous beta-amyloid-binding chaperone in the brain anddecreased levels of beta-trace in CSF may be involved in the onset andprogression of Alzheimer's disease. See, Kanekiyo et al., (2007)“Lipocalin-type prostaglandin D synthase/beta-trace is a major amyloidbeta-chaperone in human cerebrospinal fluid,” Proc. Natl. Acad. Sci. USA104(15):6412-6417. The concept provided herein of administeringartificial CSF or CSF like solution allows for the administration ofcompounds the level of which is dysregulated in the context of aneurological condition.

Provided herein are methods and devices for treating neurologicaldiseases characterized by the accumulation of inflammatory agents and/orneurotoxins. Examples of such diseases include but are not limited tocentral nervous infection, ischemic stroke, subarachnoid hemorrahge,intracerebral hemorrahge, multiple sclerosis, Parkinson's dieasetraumatic injuries and epilepsy. More particularly, these deseases arecharacterized by an accumulation of inflammatory agents such as one ormore of, typically two or more of IL-1beta and tumor necrosis factor(TNF)-alpha, IL-6, IL-8, monocyte chemoattractant protein-1,neutrophil-activating peptide 2, intracellular adhesion molecule-1,soluble Fas, tissue inhibitors of metalloproteinase 1, and matrixmetalloproteinases-2 and -9. In particular embodiment, the neurologicaldisorder is an acute brain trauma and is characterized by theaccumulation of IL-1beta and TNF-alpha. In particular embodiments, thedisease is characterized by the accumulation of a neurotoxin such asN-methyl(R)salsolinol, MPTP 6-OHDA in Parkinson's disease and glutamatein certain types of epilepsy, acrolein in multiple sclerosis.

More particularly provided herein are methods and devices for augmentingthe rate of CSF turnover, for the treatment and/or prevention of theseneurological diseases. More particularly, the methods and tools for thetreatment of these neurological diseases involve the administration ofCSF or a CSF-like solution (such as artificial CSF) directly orindirectly to the cerebral ventricles and/or to the intrathecal spacearound the spinal cord. By delivering CSF or artificial CSF to thesubarachnoid region, the rate of CSF turnover and clearance is increasedthereby enhancing removal of inflammatory agents and/or neurotoxinsaccumulating in the CSF thereby ensuring the treatment of the disease.More particularly, the methods and tools provided herein enhance theremoval of the inflammatory agents and/or neurotoxins whichcharacteristically accumulate in the CSF of patients suffering fromthese neurological conditions.

Provided herein are compositions for use in methods of prevention and/ortreatment of neurological conditions characterized by the presence ofinflammatory agents and/or neurotoxins in the CSF in a patient in needthereof and corresponding methods of treatment and prevention. Moreparticularly, a composition comprising CSF or a CSF-like solution suchas artificial CSF is provided for use in the prevention or treatment ofthese neurological conditions. In particular embodiments, the methods ofprevention and/or treatment of the neurological condition in a patientcomprise administering CSF or a CSF-like solution to the intrathecalspace or the cerebral ventricles of said patient. More particularly, theartificial CSF is administered to the intrathecal space surrounding thespinal cord. Indeed, the administration of CSF or a CSF-like solutioncan be done locally, in the cerebral ventricles, but in most embodimentsthe same effect can be achieved less invasively by infusion moreremotely, i.e. intrathecally anywhere along the spinal cord, includingthe cervical region, the thoracic region, the lumbar region etc. Inparticular embodiments, the compositions for use in the methodsdescribed herein comprise, in addition to artificial CSF one or moretherapeutic agents. In particular embodiments, such a therapeutic agentmay be an agent which is known to inhibit the inflammatory agents and/orneurotoxins present in the CSF. Examples of suitable agents capable ofinhibiting inflammatory agents are anti-inflammatory drugs such ascyclophosphamide. Examples of agents capable of inhibiting neurotoxinsinclude 3,4-dihydroxybenzalacetone or Rasagiline, inhibitors of 6-OHDA.Examples of suitable agents for inhibiting aggregation are chaperonessuch as those listed above.

Also provided herein are methods and devices for treating glaucoma. Moreparticularly, provided herein are methods and devices for increasing theICP (and thus reducing TLCPD) and/or augmenting the rate of CSFturnover, for the treatment and/or prevention of glaucoma. Morespecifically, the methods and tools for the treatment and prevention ofglaucoma described herein involve the administration of CSF or aCSF-like solution (such as artificial CSF) directly or indirectly to thecerebral ventricles and/or to the intrathecal space around the spinalcord. By delivering CSF or artificial CSF to the subarachnoid region,the ICP is increased (or the TLCPD is decreased) and/or the rate of CSFturnover and clearance in the subarachnoid space of the optic nerve isincreased (thereby enhancing removal of potentially neurotoxic wasteproducts that accumulate in the optic nerve), thus ensuring thetreatment of glaucoma.

Indeed, glaucoma can be prevented or treated from the intracranialcompartment side of the lamina instead of, or in addition to, loweringIOP. More particularly, the present inventor has found that reduced ICPcontributes to glaucoma via a mismatch in pressures across the laminacribrosa (TLCPD), such that lowering the TLCPD by manipulation of ICP byinfusion of CSF can be used to prevent and/or treat glaucoma. Moreover,the presented treatment allows an enhancement of the rate of CSFturnover which is believed to provide an additional or alternativebeneficial effect for the prevention and treatment of glaucoma.

Provided herein are compositions for use in methods of prevention and/ortreatment of glaucoma in a patient in need thereof and correspondingmethods of treatment and prevention. More particularly, a compositioncomprising CSF or a CSF-like solution such as artificial CSF is providedfor use in the prevention or treatment of glaucoma. In particularembodiments, the methods of prevention and/or treatment of glaucoma in apatient comprise administering CSF or a CSF-like solution to theintrathecal space or subarachnoid space or the cerebral ventricles ofsaid patient. More particularly, the artificial CSF is administered tothe intrathecal space surrounding the spinal cord. Indeed, theadministration of CSF or a CSF-like solution can be done locally, in thevicinity of the subarachnoid space of the optic nerve, but in mostembodiments the same effect can be achieved less invasively by infusionmore remotely, i.e. intrathecally anywhere along the spinal cord,including the cervical region, the thoracic region, the lumbar regionetc.

More particularly the method comprises administering CSF or a CSF-likesolution to a patient in need thereof so as to ensure an increase in ICPand/or to increase CSF turnover. In particular embodiments, the methodcomprises infusing CSF or a CSF-like solution to the intrathecal spaceor the cerebral ventricles so as to reduce the TLCPD, preferably to lessthan 4 mm Hg, or even lower to 1 or 2 mmHg. In particular embodiments,the method comprises infusion of CSF or a CSF-like solution such asartificial CSF into the intrathecal or subarachnoid space of a patientto ensure an ICP of between 11 and 16 mm Hg, more particularly up to 15mm Hg. However, preferably the ICP is not raised above the IOP.

Additionally or alternatively, the methods provided herein compriseensuring an increase in the total CSF turnover. The turnover of CSFdecreases substantially with aging and thus the degree of increase inturnover will need to take into consideration the age of the patient. Ina young adult, it is envisaged that the turnover is ideally about 4.0volumes/day. In particular embodiments, the methods compriseadministering the CSF or CSF-like solution to the intrathecal orsubarachnoid space of said patient by supplementing said patient's CSFwith CSF or a CSF-like solution such as artificial CSF. Moreparticularly this is ensured by way of an implantable apparatusconfigured for infusing fluid, more particularly CSF or a CSF-likesolution into the intrathecal or subarachnoid space of said patient.

In particular embodiments, it is envisaged that the CSF or CSF-likesolution may comprise a drug associated with intracranial hypertension.

According to a further aspect, also provided herein is an apparatus suchas an infusion pump for infusing CSF or a CSF-like solution into a bodycavity, more particularly into the intrathecal or subarachnoid space.The apparatus described herein can be used for the treatment and/orprevention of Alzheimer's disease, specific neurological conditions orglaucoma, more particularly open-angle glaucoma (both the normal-tensionand the high-tension form of POAG). Intrathecal infusion pumps arecurrently widely used for management of chronic pain (morphine pump) andspasticity (baclofen pump). In particular embodiments, the apparatus forinfusing fluid into the intrathecal or subarachnoid space of a patientthe apparatus comprises an implantable pump, a reservoir for containingartificial cerebrospinal fluid, an infusion catheter having an inlet endcoupled to the reservoir, and an outlet end coupled to the implantablepump and an inflow catheter. In particular embodiments the inflowcatheter has an outlet end configured to be disposed in fluidcommunication with said intrathecal or subarachnoid space, and an inletend coupled to the implantable pump; typically the implantable pump isconfigured to selectively move artificial cerebrospinal fluid from thereservoir through the infusion catheter and the inflow catheter to theintrathecal or subarachnoid space.

In particular embodiments, the device can be configured to selectivelymove artificial CSF at a rate and volume sufficient to increase theintracranial pressure and/or the cerebrospinal fluid turnover in apatient. More particularly the rate and volume of CSF infusion areadjusted so as to reduce TLCPD to a value of about 4 mm Hg or less, oreven to 2 mm Hg or 1 mm Hg (dependent on the patient). In particularembodiments, the rate and volume of artificial CSF infusion ensures anICP of between 11 and 16 mm Hg, more particularly up to 15 mm Hg.

The infusion rate ensured by the pump will be determined based ondifferent factors, including the CSF absorption rate of the patient. Inparticular embodiments, the infusion rate is adjusted to ensure anincreased turnover of CSF in the patient. In particular embodiments thepump is configured to ensure a CSF infusion rate in the range of0.05-0.1 ml/min, 0.1-0.2 ml/min, 0.2-0.42 ml/min, 0.42-0.7 ml/min oreven up to 0.7-1.04 ml/min (1.5 L/day). In particular embodiments theinfusion rate ensures a turnover of about 4.0 volumes/day.

In particular embodiments, the apparatus comprises a microcontrollerthat controls operation of the implantable pump. In particularembodiments, the microcontroller regulates the flow of the CSF orCSF-like solution through the inflow catheter.

In further embodiments, the apparatus comprises a flow sensor disposedin communication with the inflow catheter to monitor the volume and flowrate of artificial CSF pumped into the intrathecal space or cerebralventricles, wherein the microcontroller is configured to activate theimplantable pump responsive to an output of the pressure sensor.

The application further provides a combination of the apparatus asdescribed herein and an implantable pressure sensor to monitorintracranial or CSF pressure in the patient. In particular embodiments,the sensor is not physically linked to the rest of the apparatus but canbe implanted intrathecally or in the cerebral ventricles. In particularembodiments, the microcontroller of the apparatus is configured toactivate or deactivate the implantable pump responsive to an output ofthe pressure sensor. In particular embodiments, the microcontroller isconfigured to activate and deactivate the implantable pump so as toensure a constant intracranial pressure of between 11 and 16 mm Hg, moreparticularly up to 15 mm Hg. In particular embodiments, the apparatuscomprises a feedback mechanism based on the output of the pressuresensor, which ensures that the intracranial pressure does not exceed 15mm Hg.

Further described herein is the treatment and/or prevention of glaucomaby lowering the TLCPD by increasing the ICP and/or by facilitating CSFturnover which involves the infusion of CSF or a CSF-like solution asdescribed herein. In particular embodiments, this is ensured by the useof an apparatus as described herein. Although the implantation of a CSFpump is a relatively invasive intervention, it provides a worthwhilealternative for or addition to existing therapies, especially forpatients for whom non-invasive treatment options are ineffective. Inparticular embodiments, the TLCPD may be lowered by increasing the ICP.

More particularly, described herein is a method for treating and/orpreventing glaucoma, more particularly open-angle glaucoma (both thenormal-tension and the high-tension form of POAG) in a patient,comprising administering CSF or a CSF-like solution intrathecally orinto the cerebral ventricles of said patient. In particular embodiments,said method comprises providing an apparatus as described hereincomprising an implantable pump, a reservoir for containing artificialcerebrospinal fluid, an infusion catheter having an inlet end coupled tothe reservoir, and an outlet end coupled to the implantable pump; and aninflow catheter having an outlet end configured to be disposed in fluidcommunication with said intrathecal or subarachnoid space or thecerebral ventricles, and an inlet and further comprising the steps of:

-   -   providing cerebrospinal fluid or a CSF-like solution in said        reservoir;    -   coupling the inflow catheter to a region of a body cavity, more        particularly an intrathecal space or the cerebral vesicles; and    -   activating the implantable pump to pump the cerebrospinal fluid        or CSF-like fluid from the reservoir through the infusion        catheter and the inflow catheter to the body cavity at a rate        and volume sufficient to increase the ICP and/or to increase the        CSF turnover.

In particular embodiments, the body cavity is the subarachnoid space,one of the lateral ventricles, or the central canal of the spinal cord.

In particular embodiments, the pump is surgically placed under the skinof the abdomen, and delivers small, CSF or CSF-like fluid through acatheter directly into the CSF locally present. The present inventor hasfound that pumps may be provided for infusing artificial CSF, in orderto increase ICP and/or CSF turnover with the aim of treating conditionssuch as glaucoma, Alzheimer's and other neurological conditions.

In particular embodiments, the methods and tools described herein areparticularly suitable for the prevention and/or treatment of glaucoma.Prevention of glaucoma can be envisaged in patients susceptible toglaucoma such as patients having reduced intracranial pressure and/orincreased TLCPD. Examples of risk factors associated with glaucomainclude but are not limited to elevated IOP, low ICP, age, gender, highmyopica etc. Long term use of topical and systemic steroids producessecondary open-angle glaucoma by causing an increase in IOP.

Indeed, this has been confirmed by the recent observations by Zhao etal. (Physiological Reports 2015, Vol. 3(8): 1-16. Zhao et al report thatmodification of ICP dramatically altered the magnitude of retinaldysfunction induced by IOP elevation. With higher ICP levels, theyobserved protection for retinal function against IOP elevation. An ICPof 30 mmHg could completely ameliorate the total loss of retinalfunction induced by an IOP of 90 mmHg. While the IOP and ICP levels usedin that study were deliberately extreme as a proof of concept, thisconfirms the importance of ICP for retinal physiology.

In particular embodiments, the application envisages determining one ormore of the IOP, TLCPD and/or ICP in a patient prior to theadministration according to the methods described herein. This step canbe ensured in order to determine the suitability of the methods of theinvention for the prevention and/or treatment of glaucoma. Additionallyor alternatively it can be used to determine the optimal infusion rateof CSF.

Methods applied for non-invasive estimation of ICP are known in the artand include transcranial Doppler ultrasonography, tympanic membranedisplacement, ophthalmodynamometry, measurement of the orbital CSF spacearound the optic nerve, two-depth transcranial Doppler technology andothers. Two-Depth Transorbital Doppler (TDTD) measurement ofintracranial pressure quantitative absolute (ICP) value relies on thesame fundamental principle as used to measure blood pressure with asphygmomanometer. The TDTD method uses Doppler ultrasound to translatepressure balance principle of blood pressure measurement with asphygmomanometer to the measurement of ICP. The ophthalmic artery (OA),which is a vessel with intracranial and extracranial segments, is usedas pressure sensor and as a natural pair of scales for absolute ICPvalue in mmHg or mmH₂O measurement. Blood flow in the intracranial OAsegment is affected by intracranial pressure, while flow in theextracranial (intraotbital) OA segment is influenced by the externallyapplied pressure (Pe) to the eyeball and orbital tissues.

Exemplary Infusion System According to the Invention

In FIG. 1A, infusion system 100 comprises infusion catheter 30connecting reservoir 60 to pump 50, and inflow catheter 40 connectingpump 50 to cerebral ventricle V of brain B of the patient. While FIG. 1Adepicts inflow catheter 40 connecting pump 50 to the patient's brain,one skilled in the art would understand that inflow catheter may besimilarly connected to another source of CSF including the patient'sspine. System 100 provides a unidirectional path for movement ofartificial CSF to flow from reservoir 60 to brain B. Referring to FIG.1A, artificial CSF from reservoir 60 is drawn into inlet end 32 ofinfusion catheter 30 by pump 50, and expelled through outlet end 44 ofoutlet catheter 40 into brain B. Alternatively, outlet end 44″ may bedisposed in the spinal cord as depicted in FIG. 1B. While the outlet endof the inflow catheter is illustratively disposed in the cervical regionof the spine, the outlet end of the inflow catheter may be disposed inany region of the spine, including the lumbar region, the thoracicregion, etc. One-way valve 70 is positioned along infusion catheter 30or inflow catheter 40 to prevent back flow of fluid through system 100.Optional bacterial filter 85 may be positioned along infusion catheter30, inflow catheter 40, or disposed within the housing of pump 50 todestroy harmful bacteria and prevent bacteria from migrating throughsystem 100 to brain B. Alternatively, or in addition, the components ofsystem 100 may be coated or impregnated with an antibacterial orantimicrobial coating to reduce the risk of infection.

In particular embodiments, infusion catheter 30, inflow catheter 40, andpump 50 may be implanted separately and then coupled together duringimplantation of pump 50. For example, catheters 30 and 40 may beseparately implanted using a tunneling technique to place outlet end 44of inflow catheter 40 in communication with a different region of thesource of CSF. Outlet end 34 of infusion catheter 30, and inlet end 42of inflow catheter 40 then may be lead to the site for implantation ofpump 50, and coupled to the pump prior to implantation. Reservoir 60 maybe secured to a holder such as a belt and worn by the patient allowingthe patient to transport the reservoir with mobility or reservoir 60 maybe connected to infusion catheter 30 like an IV bag. Alternatively,reservoir 61 may be implantable under the skin of patient P, as depictedin FIG. 1C. In an alternative embodiment, one or more of infusioncatheter 30, inflow catheter 40, and pump 50 may be coupled togetherprior to implantation and implanted together.

Referring to FIG. 1C, reservoir 61 also may be implanted separately frominfusion catheter 31, inflow catheter 40′ and pump 50″. For example,inlet end 33 of infusion catheter 31 is placed in communication withreservoir 61 prior to being coupled to pump 50″. Reservoir 61 may beconfigured in any form suitable for placement under the skin so that itis capable of receiving artificial CSF. For example, reservoir 61 maycomprise septum 62 fluidly connected to reservoir 61 and/or port opening64 to receive artificial CSF via a syringe. Conveniently, the form ofreservoir 61 may be similar or identical to conventional implantablereservoirs of the type used for delivering a liquid therapeuticsubstance to a delivery site, such as that described in U.S. Pat. No.8,348,909 to Haase, the full disclosures of which are incorporatedherein by reference. Suitable reservoirs that may be incorporated intosystems constructed according to the present invention are availablefrom commercial suppliers, such as Medtronic PS Medical, Goleta, Calif.

As will be understood, catheters 30 and 40 comprise biocompatiblematerials, and may be provided in standard lengths or a single lengththat may be cut to size to fit a particular patient's anatomy during theimplantation procedure. Each connection in system 100 preferablyincludes a fluid-tight seal and may be accomplished through any varietyof methods as known to one of skill in the art.

Infusion catheter 30 and inflow catheter 40 may be formed from aresilient material, such as implant grade silicone or reinforcedsilicone tubing. The catheters may be reinforced along a portion oftheir length or along the entire length of the catheters. Reinforcementof the tubing may be accomplished via ribbon or wire braiding or lengthsof wire or ribbon embedded or integrated within or along the tubing. Thebraiding or wire may be fabricated from metals such as stainless steels,superelastic metals such as nitinol, or from a variety of suitablepolymers.

Outlet end 44 of inflow catheter 40 is configured to be disposed influid communication with a source of CSF. For example, outlet end 44 maybe positioned within CSF of the intrathecal space or in a cerebralventricle V of brain B of patient P. More specifically, outlet end 44may be positioned within the arachnoid membrane, the subarachnoid space,or one of the lateral ventricles. The ventricles form a group ofinterconnected cavities that are located within the cerebral hemispheresand brain stem. These ventricles or spaces are continuous with thecentral canal of the spinal cord and are similarly filled with CSF thatmay be absorbed and replenished by the body of the patient.Alternatively, artificial CSF may be infused by system 100 to replenish,flush, or both, CSF in these same spaces.

Outlet end 44 may be configured in any form suitable for placementwithin brain B so it is capable of depositing artificial CSF in acerebral ventricle. Conveniently, the form of outlet end 44 may besimilar or identical to conventional ventricular catheters of the typeused for draining CSF for treating hydrocephalus, such as thosedescribed in U.S. Pat. No. 5,385,541 to Wolff and U.S. Pat. No.4,950,232 to Ruzicka, the full disclosures of which are incorporatedherein by reference. Additionally, the form of outlet end 44 may besimilar or identical to conventional ventricular catheters of the typeused for delivering artificial CSF for treating pain or spasticity, suchas those described in U.S. Pat. Pub. Nos. 2005/0090549 to Hildebrand and201110021469 to Meythaler, respectively, the full disclosures of whichare incorporated herein by reference. Suitable ventricular cathetersthat may be incorporated into systems constructed according to thepresent invention are available from commercial suppliers, such asMedtronic PS Medical, Goleta, Calif.

Referring to FIG. 3 , one example of outlet end 44 of inflow catheter 40is described. Outlet end 44 may include multiple perforations or holes46, which preferably do not extend more than about 1 to 1.5 cm from thetip. Although a particular outlet hole arrangement is shown, otherarrangements may be used without departing from the scope of theinvention. Outlet end 44 preferably comprises biocompatible materialsuitable for implantation in the patient such as implant grade lowbending modulus material that is generally kink resistant, such assilicone or reinforced silicone, or medical shunt tubing. The tubing mayhave an outer diameter of about 2.0 mm and an inner diameter of about0.5-1.5 mm. Outlet end 44 further may comprise a flange configured topromote sealing to the brain, to allow inflow catheter 40 to pass intothe cerebral ventricles without fluid leakage.

One or more sensors may be integrated into system 100 for detectingand/or indicating a variety of fluid and/or pump parameters to othercomponents of the system or to the physician or patient. For example,outlet end 44 may further include, or be in communication with, pressuresensor 48, such as a pressure transducer, configured to monitor CSFpressure or ICP, for instance at outlet end 44 of outlet catheter 40, asshown in FIG. 3 . Pressure sensor 48 may be disposed in CSF withincerebral ventricle V of brain B and located in the vicinity of the tipof outlet end 44 of outlet catheter 40. Pressure sensor 48 need not bephysically connected to the rest of the apparatus but may be in wirelessconnection therewith. Pressure sensor 48 may be used to monitor the ICPand ensure that the ICP is sufficiently high as to obtain a normalTLCPD. Additionally, the pressure sensor may be used to monitor the ICPand ensure that the ICP is not increased to a level that increases therisk of subdural hematomas or hydrocephalus and midline shifts or thatdestabilizes the pressure in the ventricles.

In order to ensure a suitable ICP (and TLCPD), pressure sensor 48further may be configured to provide an output that is used to controloperation of pump 50. For example, pressure sensor 48 may be configuredto send a signal to microcontroller 120, in response to sensing apressure above or below a certain threshold or predetermined amount.Microcontroller 120 may be configured to control the operation of pump50 (as shown in FIG. 2 ) by activating or stopping the pump from pumpingartificial cerebrospinal fluid from the reservoir to the brain inresponse to the output of pressure sensor 48. More specifically,microcontroller 120 may activate and stop pump 50 as to obtain an ICPbetween 11 and 16 mm Hg, preferably up to 15 mm Hg.

In particular embodiments, microcontroller 120 may activate and stoppump 50 as to reduce the TLCPD (i.e. IOP minus ICP), preferably to avalue of about 4 mm Hg, preferably even less than 4 mm Hg, such as 2 mmHg or 1 mm Hg. TLCPD may be determined or estimated based on the ICP asmeasured by a sensor as described above and an (average) IOP valueobtained via a prior measurement, e.g. via tonometry as known in theart.

Inflow catheter 40 may further include flow sensor 49 to detect,measure, and/or monitor the volume and flow rate of artificial CSFpumped into the intrathecal space surrounding the spinal cord and/orinto the cerebral ventricles. Flow sensor 49 also may be configured tosend a signal to microcontroller 120 regarding the volume and flow ratein order to control pump 50. Flow sensor 49 also may be used to ensurethat system 100 is operating properly after implantation and during use.

In a preferred embodiment, microcontroller 120 coordinates and controlsoperation of the components of system 100. For example, microcontroller120 may use output signals from pressure sensor 48 and flow sensor 49 tocontrol pump 50 by turning the pump on or off or increasing ordecreasing the pump speed (and therefore the fluid flow rate). As afurther example, microcontroller 120 may stop pump 50 from pumpingartificial CSF from the reservoir into the intrathecal space surroundingthe spinal cord and/or into the cerebral ventricles when a specificvolume of artificial CSF has been pumped, unless CSF pressure or ICP isless than a threshold pressure.

Microcontroller 120 may be configured to send a signal to power source424 coupled to pump 50 to indicate when to provide or stop power to pump50 responsive to output used within system 100 to send signals betweenthe components, such as pressure sensor 48, flow sensor 49, pump 50, andmicrocontroller 120. Microcontroller 120 further may include memory 126to record operation of system 100 and/or record a specific algorithmused to infuse the artificial CSF.

As shown in FIG. 4A, outlet end 34 of infusion catheter 30 is connectedto, or coupled with inlet port 54 of pump 50. Outlet port 58 of pump 50then is connected to inlet end 42 of inflow catheter 40. Pump 50 isconfigured to control the flow rate and the infusion rate of the fluid(e.g. artificial CSF) being deposited by system 100. More specifically,pump 50 controls the flow rate from reservoir 60 through infusioncatheter 30 and into inflow catheter 40.

FIG. 4A shows an embodiment of implantable pump 50 connected to infusioncatheter 30 and inflow catheter 40. Pump 50 preferably comprises abattery-powered electromechanical pump. Further, pump 50 may be apositive displacement gear pump as described in U.S. Pat. Pub. No. US201210209165 to Degen, the entire contents of which are incorporatedherein by reference. Alternatively, pump 50 may be a diaphragm pump,piston pump, rotary pump, peristaltic pump, screw pump, or any othersuitable pump configuration. Pump 50 also may be remotely operated as isknown in the art. Pump 50 preferably is disposed in a housingmanufactured from a suitable biocompatible material, and may includebase 59 having suture holes that permit the pump to be fixed to aportion of the patient's anatomy, e.g. within the thorax or peritoneum.

FIG. 4B illustrates an alternative screw pump arrangement, suitable foruse in system 100, where screw shaft 57 is mounted for rotation withinpump 50′″ and the drive is disposed in a hermetically sealed packagemounted to the conduit exterior. The drive may be coupled to the screwshaft 57 with a gear transmission as would be apparent to one ofordinary skill in the art. Other screw pump configurations also may beuseful, such as those disclosed in U.S. Pat. No. 4,857,046 to Stevens etal. or U.S. Pat. No. 5,372,573 to Habib.

Pump 50 may be placed and secured anywhere between infusion catheter 30and inflow catheter 40, although it is preferably implanted at site thatprovides good accessibility to the surgeon and provides some protectionfor the device, once implanted. For example, pump 50 may be implantedwithin the chest or abdomen of the patient. More specifically, pump 50may be placed in the thoracic cavity and positioned in the lateralmid-thorax near the axillary line and on the under surface of a rib, andmay be held in place with sutures to the periosteum.

Referring now to FIG. 2 , pump 50 in a preferred embodiment iscontrolled by microcontroller 120. Pump 50 may operate continuously orperiodically to deposit CSF in the intrathecal space surrounding thespinal cord and/or into the cerebral ventricles. For example, pump 50may operate according to a schedule, time, or program, operate ondemand, or operate according to the sensed parameters, such as CSFpressure (ICP) or the volume pumped. Microcontroller 120 may use theoutput of pressure sensor 48 and/or flow sensor 49 to control the flowrate provided by pump 50, as discussed previously. Alternatively oradditionally, pump 50 may maintain an infusion rate of CSF at a rateselected to be equal to the natural daily absorption of CSF by thepatient to allow the body to sufficiently absorb CSF and maintain anadequate intracranial pressure. Pump 50 may maintain an infusion rate ofthe fluid in the range of 0.05-0.1 ml/min, 0.1-0.2 ml/min, 0.2-0.42ml/min, 0.42-0.7 ml/min or even up to 0.7-1.04 ml/min (1.5 L/day).

Microcontroller 120 may include clock 124 to control pump 50. Forexample, microcontroller 120 may be programmed to activate the pumpperiodically in response to clock 124 and to pump a predetermined amountof artificial CSF from reservoir 60 to cerebral ventricle V. Thepredetermined amount may be based on average or specific CSF infusionrates with respect to particular times of day, or may be specificallytitrated for a particular patient.

As depicted in FIGS. 1A and 4 , infusion catheter 30, which may besimilar in design to inflow catheter 40, connects reservoir 60 to pump50. In particular, outlet end 34 of infusion catheter 30 is coupled withinlet port 54 of pump 50.

Inlet end 32 of infusion catheter 30 is configured to be coupled toreservoir 60, so that artificial CSF is drawn through inlet end 32 intopump 50. As described above, reservoir 60 may be external to thepatient's body or implanted under the skin of the patient with means forreceiving additional artificial CSF.

One-way valve 70 may be positioned along infusion catheter 30 or inflowcatheter 40 to provide unidirectional flow of artificial CSF withinsystem 100. More specifically, one-way valve 70 allows the fluid to flowin only one direction: from the reservoir to the brain or spine. Thisprevents any backflow to the reservoir of harmful proteins from thebrain. One-way valve 70 may be located within or on infusion catheter 30or inflow catheter 40 or more preferably, may be housed within pump 50.

Examples of one-way valves suitable for use in system 100 are shown inFIGS. 5A-5C. In each of the examples, fluid may flow freely in thedirection of arrow 94. However, fluid flow opposite to the direction ofarrow 94 will force one-way valve 70 to close, thereby preventingbackflow. In order to re-open one-way valve 70, sufficient pressure inthe direction of arrow 94 must be provided, thus ensuring that fluidmoves only in the correct direction.

As shown in FIG. 5A, one-way valve 70 may comprise orifice plate 72 inseries with one-way valve 70, illustratively, duck-bill valve 74. Bothorifice plate 72 and duck-bill valve 74 may be mounted within infusioncatheter 30, inflow catheter 40 or the housing of pump 50. Flow in thedirection of arrow 94 will open duck-bill valve 74 and permit fluid flowthrough infusion catheter 30 and inflow catheter 40. One-way valve 70alternatively or additionally may comprise a variety of other flowrestrictive elements, such as a multiple orifice plate, a filterelement, or any other discrete element or combination of elements thatmay provide a flow resistance capable of yielding the flow ratesdescribed herein. FIG. 5B depicts another embodiment of one-way valve70″ comprising orifice plate 72′ in series with umbrella valve 76.Umbrella valve 76 includes an elastomeric membrane 78 that opens underpressure to permit flow in the direction of arrow 94′.

FIG. 5C depicts yet another embodiment of one-way valve 70′″ comprisingspring-loaded ball valve 71 disposed in valve seat 73. Valve seat 73also serves as an orifice to limit flow through the assembly and controlthe direction of the fluid flow. Flow in direction of arrow 94″ willopen ball valve 71 and permit flow through the orifice defined by valveseat 73.

In the above cases, the orifice may be selected to provide a desiredflow rate when the patient is in a vertical position. One-way valve 70will be implanted within the patient with a known orientation, usuallyvertical, in order to provide a known pressure head of artificial CSFonto orifice 72 or 73. This pressure will be sufficient to open theassociated one-way valve 70 and flow will be established when thepatient is in an upright position. Suitable orifice diameters in therange from 0.03 mm to 0.4 mm, preferably from 0.1 mm to 0.2 mm, fororifices having a thickness in the range from 0.001 mm to 100 mm,preferably from 1 mm to 5 mm, in order to establish average hourly flowrates in the range from 0.5 ml/hour to 15 ml/hour, preferably 1 ml/hourto 3 ml/hour.

A bacterial filter 85 may be included between inlet end 32 of infusioncatheter 30 and outlet end 44 of inflow catheter 40 to prevent bacteriafrom migrating through system 100 to the patient's brain as depicted inFIG. 1A. Although one-way valve 70 is located along infusion catheter 30or inflow catheter 40, bacterial filter 85 may be desirable to furtherprevent bacteria from reaching the brain in the event of malfunction ofpump 50. Bacterial filter 85 may be incorporated in the housing of pump50, and may include ultraviolet (“UV”) light module 84 configured toirradiate artificial CSF and destroy bacteria passing within infusioncatheter 30 and inflow catheter 40. Optionally, bacterial filter 85 maybe replaced by antibiotic or antimicrobial coatings disposed on orimpregnated within some or all of the components of system 100.

Referring again to FIG. 2 , system 100 may include extracorporealcontroller 400 that communicates wirelessly with implantable components150. Extracorporeal controller 400 may provide power to implantablecomponents 150 and/or control activation of the implantable components,such as pump 50.

Implantable components 150 may be powered by battery, or alternativelyby a super-capacitor, or other energy storage device. In a preferredembodiment, the power/energy source may be rechargeable. For example,battery 90 may be coupled to implantable inductive charging circuit 92configured to receive energy from inductive energy transmission circuit402 of extracorporeal controller 400.

Microcontroller 120 may be coupled to a first transceiver, such as radiofrequency (RF) wireless transceiver 122. Extracorporeal controller 400may be coupled to a second transceiver, such as RF transceiver 422. RFwireless transceiver 122 and RF transceiver 422 may bi-directionallycommunicate information, such as the operation of the pump, CSF pressureor ICP, and/or the desired infusion rate of the artificial CSF. Forexample, microcontroller 120 may receive programmed instructions fromextracorporeal controller 400 relating to pump activation intervals,targeted volumes of CSF to be pumped and desired flow rates.Additionally, extracorporeal controller 400 may receive data orinformation from microcontroller 120 relating to pump activationperiods, measured pressures, and actual volumes of artificial CSF pumpedthrough inflow catheter 40.

Extracorporeal controller 400 preferably includes processor 420 tocoordinate and control its various components and functions.Extracorporeal controller 400 further may include power source 424 topower the extracorporeal controller (and potentially also implantablecomponents 150), and may comprise a battery or an electrical outlet.Extracorporeal controller 400 further may include memory 426 to recordinformation, such as the information received from implantablecomponents 150 or a specific algorithm to convey to the implantablecomponents regarding the infusion of artificial CSF to the brain.

In order for the patient or the physician to enter information intosystem 100 or for system 100 to display information, extracorporealcontroller 400 preferably includes input/display device 430 and/or port432 to connect to computer 434, such as a laptop computer. Input/displaydevice 430 may include indicators or a control interface to controlsystem 100 and display detailed information about the system.Extracorporeal controller 400 optionally may wirelessly conveyor receiveinformation from computer 434, such as whether system 100 is properlyfunctioning, the current (and past) CSF pressures, the volume ofartificial CSF injected, the current (and past) flow rate of artificialCSF through the system, and/or whether pump 50 is currently activated.This information may be conveyed to the patient or physician as a visualmessage or indicator signal, such as a light or audible signal, that isinitiated once pump 50 has been activated. Computer 434 may optionallyprovide power to extracorporeal controller 400.

EXAMPLE 1 Short- and Long-Term CSF Infusion Experiments in an AnimalModel of Alzheimer's Disease

A project approval of the Dutch regulatory instances is obtained for allanimal experiments described below. The effects of CSF infusion onAβlevels are studied at a timescale of 72 hours, because the steadystate Aβlevels are reached within a few hours. This experiment iscarried out in young (pre-plaque) Aβoverexpressing mice to avoidinterference of insoluble Aβwith ELISA determination of soluble Aβ(plaques) in brain. During a stereotaxic surgery under deep anesthesia aguide cannula is implanted into the lateral ventricle. Mice are housedindividually after surgery. After at least one week of recovery, aninjector is lowered through the guide cannula, which is connectedthrough tubing to an external pump containing artificial CSF. A swivel(rotary joint) is included in the tubing, to allow the mice to movefreely around in their cage. In the first set of mice (˜5), the maximaltolerable infusion rate is established by slowly increasing the infusionrate while recording clinical signs of distress.

AD mice are bred and the short-term effect of CSF infusion on brain Aβlevels is determined. Besides the CSF-infusion group of AD mice (at maxtolerated flow rate) a control group is used to control for the effectof the surgery and presence of a guide cannula on Aβbrain levels. Givenconsiderable variation of Aβlevels between transgenic mice, at least 12mice are used in each of the groups (n=12 AD mice without infusion, n=12AD mice with CSF infusion at max flow rate). CSF infusion at maximumspeed is continued for 72 hours. Immediately thereafter, animals aresacrificed by perfusion with PBS, followed by dissection of the cortexand hippocampus. ELISA is used to determine Aβ40 and Aβ42 levels incortex and hippocampus.

To test the effect of CSF infusion in the long-term, AD mice are infusedwith CSF from the age of 12 weeks (pre-plaque) until the age at whichnormally the first plaques emerge (24 weeks of age) by surgery andinfusion techniques. To control for the effect of long-term CSFinfusion, groups of non-AD control mice are provided. Given thevariation in cognitive performance among mice, at least 16 mice are usedin each of the groups (n=16 AD mice without infusion, n=16 AD mice withCSF infusion, n=16 control mice without infusion, n=16 control mice withCSF infusion). At the age of 24 weeks, mice are tested for cognitiveperformance in a test of discrimination learning (CognitionWallautomated home cage task), as well as a test for spatial learning andmemory (Morris Water maze). Before each training session in thecognitive tests, mice are released from the CSF infusion pump, andconnected to the pump immediately following training. Hereafter, animalsare sacrificed by perfusion with PBS, dissection of the cortex andhippocampus. ELISA is used to determine Aβ40 and Aβ42 levels in cortexand hippocampus.

EXAMPLE 2 Intracranial CSF Infusion in an Animal Model of Glaucoma: theEffect on Optic Nerve and Retinal Ganglion Cell Degeneration

A primary open-angle glaucoma rat model is used to study the effect ofintracerebroventricular infusion of artificial cerebrospinal fluid onthe risk of development or the progression of glaucoma.

A project approval of the Dutch regulatory instances is obtained for allanimal experiments described below. During a stereotaxic surgery underdeep anesthesia a guide cannula are implanted into the lateralventricle. The tip of a pressure-monitoring probe (Data SciencesInternational) is fed through the cannula into the lateral ventricle toallow for measurement of intracranial pressure (ICP). Rats are housedindividually after surgery. After at least one week of recovery, aninjector is lowered through the guide cannula, which is connectedthrough tubing to an external pump containing artificial CSF. A swivel(rotary joint) is included in the tubing, to allow the rats to movefreely around in their cage. In the first set of rats (˜5), the maximaltolerable infusion rate is established by slowly increasing the infusionrate while recording clinical signs of distress. While increasing theflow rate, real-time measurements of the ICP are obtained.

After determining the maximum tolerable flow rate, four groups of rats(n=8 per group) are connected for CSF infusion at various flow rates(No, low, intermediate and maximum flow) for a duration of 1 week. Tocalculate the trans-lamina cribrosa pressure difference (intraocularpressure minus intracranial pressure), intraocular pressure as well asintracranial pressure is measured daily using a rebound tonometer(Tonolab). Hereafter, rats are sacrificed and eyes and optic nerves aredissected out and fixed for staining and analysis of optic nerve andretinal ganglion cell degeneration.

The invention claimed is:
 1. A method for prevention or treatment ofglaucoma or retinal dysfunction in a patient in need thereof, saidmethod comprising administering to said patient cerebrospinal fluid(CSF) or artificial CSF in an amount effective to maintain an increasein intracranial pressure (ICP) relative to ICP before startingadministration of the CSF or artificial CSF and to prevent or treatglaucoma or retinal dysfunction in a patient, wherein administration ofthe CSF or artificial CSF ensures an ICP between 11 and 16 mmHg in alateral decubitus position of the patient, and wherein the CSF orartificial CSF is administered to the patient using an external pumpthat is controlled by a microcontroller that activates the pump inresponse to a pressure sensor that monitors the patient's CSF pressureor ICP.
 2. The method according to claim 1, wherein CSF or artificialCSF is administered into an intrathecal space or a cerebral ventricle ofsaid patient.
 3. The method according to claim 2, wherein saidadministration reduces a trans-lamina cribrosa pressure difference(TLCPD) in said patient.
 4. The method according to claim 2, whereinsaid administration produces an increase in CSF turnover.
 5. The methodaccording to claim 1, wherein the CSF or artificial CSF is administeredby an apparatus for infusing fluid into a body cavity, the apparatuscomprising: the external pump; a reservoir containing the artificialcerebrospinal fluid; an infusion catheter having an inlet end coupled tothe reservoir, and an outlet end coupled to the external pump; and aninflow catheter having an outlet end configured to be disposed in fluidcommunication with a body cavity, and an inlet end coupled to theexternal pump, wherein the external pump is configured to selectivelymove artificial cerebrospinal fluid from the reservoir through theinfusion catheter and the inflow catheter to the body cavity at a rateand volume sufficient to replenish, flush, or both, a portion ofcerebrospinal fluid in a brain with the artificial cerebrospinal fluid,thereby increasing intracranial pressure in said patient.
 6. The methodaccording to claim 5, wherein the pressure sensor is disposed incommunication with the inflow catheter to monitor pressure of thecerebrospinal fluid.
 7. The method according to claim 5, wherein themicrocontroller includes a clock, and further is programmed to activatethe pump periodically responsive to the clock to pump a predeterminedamount of artificial cerebrospinal fluid from the reservoir to the bodycavity.
 8. The method according to claim 5, wherein the outlet end ofthe inflow catheter comprises a flange configured to promote sealing ofthe brain where the outlet catheter passes therethrough.
 9. The methodaccording to claim 5, wherein said apparatus further comprises: abattery coupled to the external pump; and an inductive charging circuitcoupled to the battery.
 10. The method according to claim 9, whereinsaid apparatus further comprises an extracorporeal controller, theextracorporeal controller including an inductive energy transmissioncircuit configured to transmit energy to the inductive charging circuit.11. The method of claim 5, wherein the microcontroller is coupled to afirst transceiver and the controller is coupled to a second transceiver,and the first and second transceiver communicate information relating tooperation of the external pump.
 12. The method according to claim 5,wherein the microcontroller receives programmed instructions from thecontroller relating to pump activation intervals and targeted volumes ofartificial cerebrospinal fluid to be pumped.
 13. The method of claim 10,wherein the extracorporeal controller receives data from themicrocontroller relating to pump activation periods, measured pressures,and actual volumes of artificial cerebrospinal fluid pumped through theinflow catheter.
 14. The method according to claim 5, wherein saidapparatus, further comprises a one-way valve disposed between thereservoir and the outlet end of the inflow catheter, the one-way valveconfigured to permit artificial cerebrospinal fluid to flow only fromthe infusion catheter to the inflow catheter.
 15. The method accordingto claim 1, wherein the artificial cerebrospinal fluid comprises one ormore therapeutic agents.
 16. The method according to claim 5, whereinthe reservoir is adapted to be implanted within the patient.
 17. Themethod according to claim 1, wherein the artificial CSF comprises sodiumions at a concentration of 140-190 mM, potassium ions at a concentrationof 2.5-4.5 mM, calcium ions at a concentration of 1-1.5 mM, magnesiumions at a concentration of 0.5-1.5 mM, phosphor ions at a concentrationof 0.5-1.5 mM, and chloride ions at a concentration of 100-200 mM.